Incorporating potency into EU classification for carcinogenicity and reproductive toxicity.

Although risk assessment, assessing the potential harm of each particular exposure of a substance, is desirable, it is not feasible in many situations. Risk assessment uses a process of hazard identification, hazard characterisation, and exposure assessment as its components. In the absence of risk assessment, the purpose of classification is to give broad guidance (through the label) on the suitability of a chemical in a range of use situations. Hazard classification in the EU is a process involving identification of the hazards of a substance, followed by comparison of those hazards (including degree of hazard) with defined criteria. Classification should therefore give guidance on degree of hazard as well as hazard identification. Potency is the most important indicator of degree of hazard and should therefore be included in classification. This is done for acute lethality and general toxicity by classifying on dose required to cause the effect. The classification in the EU for carcinogenicity and reproductive toxicity does not discriminate across the wide range of potencies seen (6 orders of magnitude) for carcinogenicity and for developmental toxicity and fertility. Therefore potency should be included in the classification process. The methodology in the EU guidelines for classification for deriving specific concentration limits is a rigorous process for assigning substances which cause tumours or developmental toxicity and infertility in experimental animals to high, medium or low degree of hazard categories by incorporating potency. Methods are suggested on how the degree of hazard so derived could be used in the EU classification process to improve hazard communication and in downstream risk management.

Potency values from the local lymph node assay: application to classification, labelling and risk assessment.

Hundreds of chemicals are contact allergens but there remains a need to identify and characterise accurately skin sensitising hazards. The purpose of this review was fourfold. First, when using the local lymph node assay (LLNA), consider whether an exposure concentration (EC3 value) lower than 100% can be defined and used as a threshold criterion for classification and labelling. Second, is there any reason to revise the recommendation of a previous ECETOC Task Force regarding specific EC3 values used for sub-categorisation of substances based upon potency? Third, what recommendations can be made regarding classification and labelling of preparations under GHS? Finally, consider how to integrate LLNA data into risk assessment and provide a rationale for using concentration responses and corresponding no-effect concentrations. Although skin sensitising chemicals having high EC3 values may represent only relatively low risks to humans, it is not possible currently to define an EC3 value below 100% that would serve as an appropriate threshold for classification and labelling. The conclusion drawn from reviewing the use of distinct categories for characterising contact allergens was that the most appropriate, science-based classification of contact allergens according to potency is one in which four sub-categories are identified: 'extreme', 'strong', 'moderate' and 'weak'. Since draining lymph node cell proliferation is related causally and quantitatively to potency, LLNA EC3 values are recommended for determination of a no expected sensitisation induction level that represents the first step in quantitative risk assessment.

Numerical dosimetry ELF: accuracy of the method, variability of models and parameters, and the implication for quantifying guidelines.

In situ electric fields and current densities are investigated by numerical simulations for exposure to ELF electric and magnetic fields. Computations are based on the finite-difference time-domain method (FDTD). The computational uncertainty is determined by comparison of analytical and numerical results and amounts to a worst-case expanded uncertainty (95% confidence interval) of +/-9.89 dB for both dosimetric quantities (E, J). Detailed investigations based on the Visible Human body model with a resolution of 2 mm show a strong influence of the tissue boundaries on the simulation results, which is caused by the numerical method. For the tissue specific in situ electric field and current density changes in excess of 10 dB are observed when comparing the results with and without evaluation of the dosimetric quantities at tissue boundaries. Moderate sensitivities with respect to tissue boundaries are observed only for low conductivity tissues when evaluating the in situ electric field whereas this behavior is observed for high conductivity tissues when evaluating the current density. For exposure to a 50 Hz magnetic field corresponding to the ICNIRP reference level, the simulated current density for central nervous system (CNS) tissue is in compliance with the ICNIRP guidelines. Exposure to a 50 Hz electric field may exceed the ICNIRP basic restriction for CNS tissue at least in a worst-case scenario (grounded human body, vertical electric field, tissue boundaries included for the evaluation of the current density). The in situ electric field is the more stable dosimetric quantity with respect to changes of the tissue conductivity of the Visible Human body model. The maximum conductivity sensitivity coefficient amounts to +122% for the current density whereas the maximum sensitivity coefficient for the in situ electric field is -20%. For electric field exposure the in situ electric field remains comparable (-6% to -4%), the averaged current density change ranges from -57% to -16% for the tissues under investigation. Magnetic field exposure of a scaled model of a five year old child leads to a decrease of the dosimetric quantities (J: -74% to -45%, E: -42% to -23%) compared to the Visible Human results.